Diminished growth, deformity, osteopenia noted on plain radiographs, and frequent osteoporosis-related fractures are evidence of problems with bone growth and metabolism in many children with an assortment of medical and physical conditions. Although these very late consequences are clinically apparent, the problems are usually initially silent during the important years of skeletal growth and development. The Midcareer Award is requested to support the Research Plan of Dr. Richard Henderson, MD, PhD. He is Professor of Orthopaedics and Pediatrics at the University of North Carolina, and in this capacity is a clinically active pediatric orthopaedic surgeon. Dr. Henderson also has a long-standing commitment to clinical research, with proven productivity. His primary research focus is on the issues of osteoporosis, fractures, and bone growth and metabolism in various pediatric conditions such as cerebral palsy, cystic fibrosis, milk allergy, chemotherapuetically treated malignancies, and muscular dystrophy. In the first phase of his Research Plan techniques for assessing bone growth, density, and metabolism are adapted to the unique features of handicapped children. The first phase also includes several single-site, observational, cross-sectional and longitudinal studies with the specific aim of assessing the potential impact of these assorted conditions on mineralization of the immature skeleton. This phase of the Research Plan has just been completed. The second phase includes projects designed to better characterize bone growth and metabolism in children with cerebral palsy, and to assess in greater detail the prevalence, causes, and outcomes of osteoporosis in this population. The utility of this information depends in great part on the availability of prevention and/or treatment alternatives. The bisphosphonates are a class of medications used for the treatment of osteoporosis in elderly adults, and limited anecdotal data suggest that these drugs are also effective in children. The second phase of the Research Plan includes the first controlled clinical trial assessing the safety and efficacy of these drugs in a pediatric population. Extensive collaboration with other research centers brings greater statistical power and expertise in nutrition to studies in the second phase. The second phase consists of 5 closely inter-related projects over a 2-3 year time span, and data collection recently began in April 1998. The third phase planned for the years 2001-2004 will involve larger-scale clinical trials assessing bisphosphonates for the treatment of osteoporosis in multiple pediatric conditions. The practicalities of drug treatment in clinical practice and the dose-response relationship are important issues that will be addressed in this phase. The Midcareer Award is requested to support the second and third phases of the Research Plan.